The goal of this proposal is to examine the physiological function of the GABA-B-mediated slow IPSP in the hippocampus. The slow IPSP, as one of the two known GABA-mediated inhibitory synaptic potentials, contributes to the balance of excitation and inhibition required for the maintenance of non-epileptiform activity in the hippocampus, and for the normal flow of information involved in acquiring new memories or for learning new behaviors. While the role of the GABA-A-mediated fast IPSP in the prevention of epileptiform burst activity is well known, very little is presently known about the function of the slow IPSP. Understanding the slow IPSP requires a detailed investigation of the type(s) of cells responsible for producing it, their synaptic inputs and axonal projections, distribution of appropriate receptors on target neurons, and an examination of the molecular and physiological mechanisms that are activated on the postsynaptic membrane. Obtaining such data using in vivo preparations, or even acutely prepared hippocampal slices or dissociated neuronal cultures, has been very difficult. We have been successful, however, in employing the "cultured slice" preparation to begin to analyze the slow IPSP and its role in preventing epileptiform activity. We propose, in this application, to use the hippocampal slice culture preparation to test the following hypotheses: 1. The population of interneurons responsible for the slow IPSP is distinct from the interneurons mediating the fast IPSP. 2. Terminals of the slow IPSP-generating interneurons synapse preferentially on pyramidal cell dendrites. 3. There is a higher density of synaptically activated GABA-B receptors on pyramidal cell dendrites than on pyramidal cell somata. 4. Direct activation of single interneurons involved in slow IPSP production can alter the period and duration of slow IPSPs. Modifying slow IPSPs can effect the formation of epileptiform bursts. 5. Noradrenergic and cholinergic innervation of the hippocampus modulate interneurons responsible for producing slow IPSPs. In addition, there is an interaction between postsynaptic responses produced by activation of GABA-B and NA or ACh receptors.